The epigenetic regulator Mll1 is required for Wnt-driven intestinal tumorigenesis and cancer stemness.
The epigenetic regulator Mll1 is required for Wnt-driven intestinal tumorigenesis and cancer stemness.
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表观遗传调节因子Mll 1是Wnt驱动的肠道肿瘤发生和癌症干性所必需的。
DOI：
10.1038/s41467-020-20222-z
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发表时间：
2020-12-21
影响因子：
16.6
通讯作者：
Birchmeier W
中科院分区：
文献类型：
--
作者：
Grinat J;Heuberger J;Vidal RO;Goveas N;Kosel F;Berenguer-Llergo A;Kranz A;Wulf-Goldenberg A;Behrens D;Melcher B;Sauer S;Vieth M;Batlle E;Stewart AF;Birchmeier W
Wnt/β-Catenin信号转导通路在肠道癌变和肠癌干细胞的维持中起着至关重要的作用。在这里，我们确定组蛋白甲基转移酶M111是WNT驱动的肠癌的调节因子。MLL1在LGR5+干细胞和人结肠癌中高表达，并伴有核β-连环蛋白的增加。高水平的MLL1与结肠癌患者的生存不良有关。在小鼠中，mll1的基因消融可以防止Wnt/β-catenin驱动的Lgr5+肠道干细胞形成腺瘤。MLL1的消融减少了人结肠癌球体的自我更新，并阻止了异种移植瘤的生长。MLL1控制干细胞基因的表达，包括Wnt/β-catenin靶基因Lgr5。当MLL1缺失时，干细胞启动子上的组蛋白甲基化从激活H3K4三甲基化转变为抑制H3K27三甲基化，表明MLL1通过多梳抑制复合体2(PRC2)介导的H3K27三甲基化来拮抗基因沉默来维持干细胞基因的表达。Wnt突变的肠道肿瘤启动细胞的转录组图谱显示，M111调节Gata4/6转录因子，已知维持癌症干细胞和控制杯状细胞分化。我们的结果表明，MLL1是Wnt/β-catenin诱导的肠道肿瘤和肿瘤干性的重要表观遗传调节因子。肠癌干细胞(CSC)与结肠癌有关。在这里，作者表明，CSC中的Wnt/β-catenin信号需要表观遗传调节因子M111来促进小鼠和人类结肠癌模型的干性和肿瘤发生。
Wnt/β-catenin signaling is crucial for intestinal carcinogenesis and the maintenance of intestinal cancer stem cells. Here we identify the histone methyltransferase Mll1 as a regulator of Wnt-driven intestinal cancer. Mll1 is highly expressed in Lgr5+ stem cells and human colon carcinomas with increased nuclear β-catenin. High levels of MLL1 are associated with poor survival of colon cancer patients. The genetic ablation of Mll1 in mice prevents Wnt/β-catenin-driven adenoma formation from Lgr5+ intestinal stem cells. Ablation of Mll1 decreases the self-renewal of human colon cancer spheres and halts tumor growth of xenografts. Mll1 controls the expression of stem cell genes including the Wnt/β-catenin target gene Lgr5. Upon the loss of Mll1, histone methylation at the stem cell promoters switches from activating H3K4 tri-methylation to repressive H3K27 tri-methylation, indicating that Mll1 sustains stem cell gene expression by antagonizing gene silencing through polycomb repressive complex 2 (PRC2)-mediated H3K27 tri-methylation. Transcriptome profiling of Wnt-mutated intestinal tumor-initiating cells reveals that Mll1 regulates Gata4/6 transcription factors, known to sustain cancer stemness and to control goblet cell differentiation. Our results demonstrate that Mll1 is an essential epigenetic regulator of Wnt/β-catenin-induced intestinal tumorigenesis and cancer stemness. Intestinal cancer stem cells (CSC) are associated with colon cancer. Here, the authors show that Wnt/beta-catenin signalling in CSC requires the epigenetic regulator Mll1 to promote stemness and tumourigenesis in murine and human colon cancer models.
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影响因子：
56.9
作者：
Behrens, J;Jerchow, BA;Birchmeier, W
通讯作者：
Birchmeier, W
实现癌症基因组数据的共同愿景。
DOI：
10.1056/nejmp1607591
发表时间：
2016-09-22
期刊：
The New England journal of medicine
影响因子：
--
作者：
Grossman RL;Heath AP;Ferretti V;Varmus HE;Lowy DR;Kibbe WA;Staudt LM
通讯作者：
Staudt LM
影响因子：
4.6
作者：
Andreu, P;Colnot, S;Romagnolo, B
通讯作者：
Romagnolo, B
DOI：
10.1083/jcb.200311021
发表时间：
2004-07-05
期刊：
The Journal of cell biology
影响因子：
--
作者：
Blache P;van de Wetering M;Duluc I;Domon C;Berta P;Freund JN;Clevers H;Jay P
通讯作者：
Jay P
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J